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The gastric secretory trefoil factor family (TFF) peptides xP1 and xP4 are the Xenopus laevis orthologs of mammalian TFF1 and TFF2, respectively. The aim of this study was to analyze the molecular forms of xP1 and xP4 in the X. laevis gastric mucosa by FPLC. xP1 mainly occurred in a monomeric low-molecular-mass form and only a minor subset is associated with the mucus fraction. The occurrence of monomeric xP1 is unexpected because of its odd number of cysteine residues. Probably a conserved acidic residue flanking Cys55 allows monomeric secretion. Furthermore, Cys55 is probably post-translationally modified. For the first time, we hypothesize that the free thiol of monomeric xP1-and probably also its mammalian ortholog TFF1-could have a protective scavenger function, e.g., for reactive oxygen/nitrogen species. In contrast, xP4 mainly occurs in a high-molecular-mass form and is non-covalently bound to a mucin similarly as TFF2. In vitro binding studies with radioactively labeled porcine TFF2 even showed binding to X. laevis gastric mucin. Thus, xP4 is expected to bind as a lectin to an evolutionary conserved sugar epitope of the X. laevis ortholog of mucin MUC6 creating a tight mucus barrier. Taken together, xP1 and xP4 appear to have different gastric protective functions.
Figure 1. Schematic representation of the (TFF) peptides xP1 and xP4 consisting of 55 and 207 amino acids, respectively. The conserved cysteine residues including disulfide bridges are shown in yellow. The N-glycosylation site in xP4.1 is indicated by a hexagon, which is missing in xP4.2.
Figure 2. FPLC purification and analysis of xP1 and xP4 from a X. laevis gastric extract. (A) Elution profile after SEC on a Superdex 75 HL column as determined by absorbance at 280 nm (PAS-positive mucin fractions: pink). (B) Distribution of the relative xP1 (blue) and xP4 content (red) as determined by Western blot analysis under reducing conditions and semi-quantitative analysis of the typical 7k-and 25–30k double band intensities, respectively. (C) 15% SDS-PAGE and subsequent Western blot analysis of the low-molecular-mass fractions D3–D9 and the fractions B8/C10/D5, respectively. Samples were analyzed under reducing (R) and non-reducing conditions (NR), respectively, for their xP1 immunoreactivity. Molecular mass standard: left. (D) 15% SDS-PAGE and subsequent Western blot analysis of high-molecular-mass fractions B6/B11. Samples were analyzed under reducing (R) and non-reducing conditions (NR), respectively, for their xP4 immunoreactivity. The molecular mass standard is indicated on the left. (E) 1% AgGE and subsequent Western blot analysis of high-molecular-mass fractions B5–C1. Shown are reactivities for xP1, xP4, GSA-II and (F) the hybridization signals (autoradiography) obtained after incubating the blot with 125I-labeled porcine pancreatic TFF2 (overlay assay). The start is marked with a dot on the left.
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